Vogt-Koyanagi-Harada disease following ChAdOx1 nCoV-19 and mRNA-1273 vaccination

Abstract

Almost all vaccines have been reported to be associated with ocular inflammation, which has caused some concern regarding global mass COVID-19 vaccination efforts. Vogt-Koyanagi-Harada disease (VKHD) is a granulomatous inflammation caused by an autoimmune response against antigens in melanocytes, including those in the eyes. The mechanism by which COVID-19 vaccines are associated with VKHD is still unclear. Here, we report two cases of VKHD following COVID-19 vaccination. The first is a case of probable VKHD that presented with bilateral vision loss after administration of the adenovirus-vectored vaccine ChAdOx1 nCoV-19 (AstraZeneca). The condition improved after intravenous methylprednisolone 1 g daily for 3 days, followed by oral methotrexate and a slow taper of oral corticosteroids. The second case is a patient with an established diagnosis of well-controlled VKHD who developed a reactivation of the disease after receiving the mRNA-based vaccine (mRNA-1273, Moderna). VKHD is a potential ocular event that could follow COVID-19 vaccination. Awareness of this association is key to early detection and treatment to prevent loss of vision.

Since the outbreak of SARS-CoV-2 (COVID-19) in late December 2019, billion people worldwide have been infected and died. Many COVID-19 vaccines have been developed and approved for emergency use to control the infection and stop the pandemic. Minimal information about adverse events after vaccine administration is known.

Several case series of patients diagnosed with an ocular inflammatory event following COVID-19 vaccination are being reported. The most common events are anterior uveitis, followed by posterior uveitis and scleritis [1].

Nearly all vaccines have been reported to be associated with uveitis. According to three surveillance systems: the National Registry of Drug-Induced Ocular Side Effects, the Uppsala Monitoring Center (UMC), and the Vaccine Adverse Event Reporting System (VAERS), the hepatitis B vaccine was reported to be the most common vaccine-induced uveitis, followed by immunization for human papillomavirus and influenza virus [2]. Many hypotheses have been proposed for vaccine-associated uveitis:

• •molecular mimicry secondary to a close resemblance between vaccine peptide fragments and uveal self-peptides;
• •delayed-type hypersensitivity with deposition of immune complexes;
• •an immune reaction to vaccination adjuvants [2].

We report two cases of Vogt-Koyanagi-Harada disease (VKHD) after administration of COVID-19 vaccines. The first case is a new-onset VKHD following the adenovirus-vectored vaccine ChAdOx1 nCoV-19 (AstraZeneca), and the second case is a patient with reactivation of the disease after receiving the mRNA-based vaccine (Moderna).

Patient 1

A 59-year-old male presented to the Ophthalmology Department with blurry vision in both eyes (OU) for 6 weeks. The vision started to decrease 2 weeks after the second dose of the adenovirus-vectored vaccine ChAdOx1 nCoV-19 (AstraZeneca). He had hearing loss since he was a child and had been using a hearing aid. He denied any other ocular or systemic symptoms. He had no underlying diseases, history of ocular trauma, or previous ocular surgery. On examination, his best corrected visual acuity (BCVA) was light perception OU. The intraocular pressure (IOP) was 14 mmHg OU. Anterior segment examination revealed a dense cortical cataract without anterior chamber cell OU. There were no vitreous cells. Fundus examination showed multifocal serous retinal detachments that were extensive in the inferior and optic disc hyperemia OU. There was no retinitis, choroiditis or vasculitis. Spectral domain optical coherence tomography (OCT) demonstrated bilateral serous retinal detachments with subretinal septa, subretinal hyperreflective dots, subretinal membranes and retinal pigment epithelium (RPE) folds (Fig. 1 ). Fundus fluorescein angiography (FFA) showed multiple hyperfluorescent pinpoint foci of leakage and optic disc leakage OU. Indocyanine green angiography (ICGA) showed hypofluorescent dark dots OU (Fig. 2 ). Systemic workup for other causes of ocular inflammation, including infective and autoimmune causes, was unremarkable. According to the revised diagnostic criteria for VKHD, this patient was diagnosed with probable VKHD and treated with intravenous methylprednisolone 1 g each day for 3 days, followed by oral corticosteroids 1 mg/kg/day with slow tapering. Methotrexate (MTX) was started at a dose of 7.5 mg once weekly. His BCVA at the 2-week follow-up visit improved to 20/70 OU, and OCT showed a reduction in subretinal fluid OU. The dose of MTX increased to 12.5 mg once weekly.

Figure 1.

The optical coherence tomography image shows serous retinal detachments with subretinal septa, subretinal hyperreflective dots, subretinal membranes and retinal pigment epithelium folds in both eyes (A). Fundus fluorescein angiography shows multiple hyperfluorescent pinpoint foci of leakage and optic disc leakage in both eyes. Indocyanine green angiography shows hypofluorescent dark dots in both eyes (B).

Figure 2.

Mutton fat keratic precipitates.

Patient 2

A 31-year-old female complained of decreased vision in both eyes 1 week after receiving the third dose of mRNA-based vaccine (mRNA-1273, Moderna). Her first and second doses of COVID-19 vaccines were inactivated virus vaccines (CoronaVac, Sinovac). She had been treated for VKHD for 14 months. Her current medications included azathioprine 2 mg/kg/day, cyclosporine 4 mg/kg/day, mycophenolate mofetil 500 mg and prednisolone 2.5 mg. The disease had been controlled with no signs of active inflammation for 5 months. Twelve days after vaccination, BCVA was 20/20 OU. IOP was 15 mmHg in the right eye (OD) and 16 mmHg in the left eye (OS). A slit-lamp examination showed mutton fat keratic precipitates and 2+ cells in the anterior chamber OU. There were no cells in the vitreous cavity. Subretinal fluid was not present on OCT. Topical corticosteroids were given, and then anterior chamber cells gradually decreased. Clearance of anterior chamber cells was achieved 4 weeks later without an increase in systemic immunosuppressive agents.

Discussion

VKHD is a multisystem granulomatous inflammation that affects pigmented tissues, such as the eye, inner ear, meninges, skin and hair [3]. The proposed pathogenic mechanism is due to the T-cell-mediated autoimmune process against antigens in melanocytes [4]. A diagnosis is based on clinical manifestations and ancillary tests after excluding other diseases.

Several VKHD cases, including new-onset disease or worsening of a previously controlled disease after COVID-19 vaccination, have been reported. In all reporting cases, related vaccines included the viral vector-based vaccine (ChAdOx1 nCoV-19, AstraZeneca) [5], the mRNA-based vaccines (mRNA-1273, Moderna; and BNT162b2, Pfizer-BioNTech) [6], [7], [8], and inactivated virus vaccines (CoronaVac, Sinovac and Vero cell, Sinopharm) [9], [10]. Saranceno et al. reported a case of a 62-year-old female diagnosed with VKHD after receiving a viral vector-based vaccine, ChAdOx1 nCoV-19. She developed acute bilateral visual loss 4 days after vaccination [5]. Our patient (patient 1) developed bilateral visual loss 14 days after vaccination. Additionally, the mRNA-based COVID-19 vaccine mRNA-1273 (Moderna) has been reported to be linked to a new-onset VKHD, as described by Joo and colleagues [6]. In our second patient, the mRNA-based vaccine (mRNA-1273, Moderna) was associated with an activation of ocular inflammation in a previous well-controlled VKHD. In terms of reactivation, two cases have been described after mRNA-based vaccination (BNT162b2, Pfizer-BioNTech) [7], [8].

There are many hypotheses regarding the pathogenesis of COVID-19 vaccines and the occurrence or reactivation of VKHD. Induction of nonspecific autoreactive CD4+ and CD8+ T cells either by adjuvants in mRNA-based vaccines or COVID-19 vaccination itself has been proposed [6], [11]. Lipid nanoparticle adjuvants used in BNT162b2 or mRNA-1273 have been shown to induce innate and adaptive immunity through various mechanisms, resulting in specific CD4+ and CD8+ T cells and memory B cell production accounting for protective immunogenicity. However, these potent adjuvants also induce a nonspecific type I interferon response and interleukin-6 production responsible for local and systemic reactogenicity [12]. Despite these reports, there is no definite proof from in vivo or in vitro models demonstrating such an excessive and nonspecific immune response to the pathogenesis of VKHD. Moreover, the viral vector-based vaccine ChAdOx-1 nCoV-19 (AstraZeneca) contains no adjuvant, so adjuvant-induced VKHD may not account for all pathogenic mechanisms. Molecular mimicry between SARS-CoV-2 antigens and the melanocyte hypothesis is very unlikely due to the extreme rarity, with only two case reports of VKHD followed in millions of confirmed COVID-19 cases [13], [14]. According to these data, further observations and investigations are required to better define the underlying pathogenic mechanism of COVID-19 vaccine-induced VKHD.

To the best of our knowledge, we reported the second case in which VKHD occurred after adenovirus vectored vaccine ChAdOx1 nCoV-19 (AstraZeneca) [5], the second case after mRNA-1273 (Moderna) vaccination [6], and the third case of disease reactivation [7], [8].

Conclusion

As massive COVID-19 vaccination continues globally, adverse events from COVID-19 vaccines have increasingly been reported, including ocular adverse events. However, the benefits of COVID-19 vaccination should outweigh the potential risks from rare and nonfatal ocular inflammation, which can subsequently be controlled with thorough care and medication adjustment. Our cases alert clinicians’ awareness of a potential association from COVID-19 vaccines among uveitis patients.

Funding

The authors received no financial support for the research.

Disclosure of interest

The authors declare that they have no competing interest.